Amiodarone for chronic heart failure

simpler to evaluate because there is only one main outcome-published papers. These articles can be evaluated not only in terms of how many and where they are published but also according to whether they are read and cited. There is general agreement that a mere quantitative approach is grossly inadequate. The journal in which a paper is published is immensely important. There are few high quality journals: a mere 347 of the 4398 science journals (8%) in the Journal Citation Index garnered 54% of all citations (unpublished data derived from JCI). These results correlate with data from perusal of scientific journals in librariesnumerous studies have shown that 10% of journal titles account for 80% of use. With respect to citation of articles, only 45% of all papers in the Science Citation Index between 1981 and 1985 were cited one or more times.3 An insight into the quality of published information is provided by Williamson and colleagues.4 Their experimental design was developed with the aid of a complex MEDLINE search which provided 1000 citations, of which only 150 were found to be relevant, and only 3 of those were methodologically sound. In the USA, as in the UK, grant-making is not the sole purview of the government. Foundations have an important role, and none of them adheres to NIH’s draconian requirements for grant proposals. Most recommend an initial one or two page letter, followed by a brief application with a curriculum vitae and some letters of recommendation. Furthermore, foundation officers will often seek out the best people and encourage them to submit a proposal. In the UK, the Wellcome Trust’s annual expenditure, of the order of 200 to 300 million dollars, approaches that of the Medical Research Council (MRC), whose role is similar to that of NIH. The Trust sends its applications (no more than five pages) to several reviewers, and makes a final decision through panels of experts. To evaluate its biomedical research grants and those of other funding agencies including the MRC, the Trust has initiated a research outputs database that records the publications of all British and Irish scientists and their sources of support. In the USA, the Howard Hughes Medical Institute’s (HHMI) expenditure ($300 million in 1993) is similar to that of the Wellcome Trust, but only about 4% of that of NIH. As an institute without walls, HHMI conducts research in its laboratories headed by 222 investigators located at 53 institutions in 23 states. HHMI is now producing over 20% of the 200 mostcited biomedical papers.5 The Rockefeller Foundation’s Great Neglected Diseases of Mankind (GND) programme convinced fourteen outstanding research laboratories (three in

the third world) to work on the health problems of the developing world by providing substantial annual funding for eight years, with freedom to work on whatever interested them. At the end of that time a bibliometric analysis of the GND’s 1280 publications showed that the mean impact factor (annual citations divided by annual articles) for the journals in which they were published was 3-94 (only 130 of the more than 4000 journals in the Science Citation Index had impact factors greater than that). When Jonathan Cole, the sociologist of science, spoke highly of the Rockefeller Foundation’s programme, a rejoinder was "Sure, they only supported the best people", a declaration that is also applicable to the HHMI. Warren Weaver, the remarkable philanthropist who, among other things, virtually created molecular biology through his unique approach to grant-making, said "it is necessary to look at the intellectual capacity, the record of imagination of dedication and interest of the man who proposes to do the work. The written specification of the problem is almost always unimportant ... A horribly precise and extensive statistical plan by somebody who does not have the intellectual competence to do a good job is nothing but a snare and delusion. The application, even if it is in

triplicate, really never proves anything."

1 2 3 4

5

Marshall E. NIH tunes up peer review. Science 1994; 263: 1212-13. Marshall E. Peer review reforms get good review. Science 1994; 265: 467. Hamilton DP. Publishing by-and for?—the numbers. Science 1990; 250: 1331-32. Williamson JW, German PS, Weiss R, Skinner EA, Bowes F. Health science information management and continuing education of physicians. Ann Intern Med 1989; 110: 151-60. Hughes investigators now field 1 in 4 top papers. Science Watch 1994; 5: 7.

COMMENTARY

Amiodarone for chronic heart failure See page 493

In this issue GESICA (Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina) report a welldocumented two-year trial of amiodarone in some 500 patients with moderately severe stable heart failure of mixed aetiology. Patients were randomised to "low dose" (300 mg daily) or no amiodarone, and were analysed on an intention-to-treat basis with a primary end-point of mortality. Randomisation was stratified with respect to non-sustained ventricular tachycardia. Maintenance treatment for heart failure included digitalis, diuretics, and enalapril in almost all patients, but not antiarrhythmic drugs. Of the 260 patients on amiodarone 87 died but there were 106 deaths in the 256 controls, a difference which translates to a risk reduction of about 30%. The difference appeared after 3 months, was similar

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for sudden and for progressive heart failure deaths, and consistent across subgroups defined by symptomatic severity. Amiodarone was also associated with a significant improvement in functional capacity. Only 12 patients had to stop amiodarone because of side-effects, related mostly to sinus bradycardia; monitoring for symptomless side-effects was not undertaken. This is a striking and convincing result and looks like a firm step on the road towards considering routine addition of amiodarone to the standard treatment of moderately severe chronic heart failure. The potential of antiarrhythmic drugs to prolong survival in heart failure by preventing sudden death is not a new idea. Many deaths are sudden. Ventricular arrhythmias are common and generally associated with increased mortality.’ "Routine" antiarrhythmic therapy has been tainted by the outcome of the CAST study but several papers have reported that amiodarone reduces ventricular arrhythmias in heart failure, with lower mortality in most. The GESICA trial is the first demonstrate that amiodarone prospectively to in heart failure. The size of reduces mortality significantly the reduction surprised the organisers, who halted the trial two-thirds of the way through its planned course because of an interim analysis. The fortunes of amiodarone have oscillated more than those of most drugs. Introduced some 20 years ago as an antianginal agent, amiodarone had its second coming as an antiarrhythmic drug. Its very efficacy led to uncritical overprescription. Then came growing awareness of its side-effects (arrhythmogenic, pulmonary, gastrointestinal, and ocular, thyroid, neurological, hepatic, dermatological), very long biological half-life, and potentially dangerous potentiation of other drug effects, notably of warfarin and digoxin.3 We learned to reserve amiodarone for life-threatening and intractable arrhythmias, to use lower doses (side-effects are mostly dose-related and cumulative), and to monitor its effects. The paucity of symptomatic side-effects in GESICA may was

surprise cardiologists (are Argentinian patients different?). side-effects would have been identified by investigative monitoring; some may become more serious with longer treatment. Other studies report up to 30% More

withdrawals due to side-effects with 200-400 mg amiodarone daily. There is also an unresolved concern that amiodarone may increase the risk of postoperative pulmonary complications and thus be contraindicated for potential transplant candidates.4 The disadvantages of these potential side-effects are heavily counterbalanced by the reduction in mortality, but what of the impact of side-effects in longer term survivors? Sins of commission generally weigh more heavily than sins of omission. Lower dosage is unlikely to be the answer: one heart failure trial of 200 mg amiodarone daily resulted in fewer side-effects but no reduction of 1-year mortality." The benefits of amiodarone in GESICA do not seem to be attributable entirely to prevention of sudden death: functional capacity improved and the reductions in sudden and progressive heart failure deaths were similar. Slowing of heart rate, vasodilation, and non-specific adrenergic blockade may have tempered the deterioration of cardiac function that characterises chronic heart failure. Notably the beneficial effects of amiodarone on mortality and cardiac function were in addition to those that may

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have accrued from full standard conventional treatment. They could thus be applicable to the generality of patients with chronic heart failure. Clinicians tend to feel uneasy at applying the blunt instrument of standard guidelines directed at therapeutic manipulation of epidemological outcome-it is not so easy to monitor the response as in the symptomatic treatment of their individual patients. Amiodarone may prove to be an important addition to the routine management of chronic heart failure. However, it seems prudent to await confirmatory trials with longer follow-up and monitoring, together with continuing efforts to identify subgroups who might stand to benefit most or be most at risk. A H Henderson Department of Cardiology, University

of Wales

College of Medicine,

Cardiff, UK 1

2

Dargie HJ, Cleland JGF, Leckie BJ, Inglis CG, East BW, Ford J. Relation of arrhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987; 76 (suppl IV): IV-98-107. Chatterjee K. Amiodarone in chronic heart failure. JACC 1989; 14: 1775-76.

3

Wilson JS, Podrid 121: 158-71.

4

Chelimsky-Fallick C, Middlekauff HR, Stevenson WG. et al. therapy does not compromise subsequent heart transplantation. JACC 1992; 20: 1556-61. Nicklas JM, McKenna WJ, Stewart RA, et al. Prospective, doubleblind, placebo-controlled trial of low-dose amiodarone in patients with severe heart failure and asymptomatic frequent ventricular ectopy. Am Heart J 1991; 122: 1016-21.

PJ.

Side effects from amiodarone. Am

Heart J 1991;

Amiodarone

5

Treating myocardial infarction: importance of early reperfusion Various trials of thrombolysis in acute myocardial infarction have emphasised the importance of early reperfusion. In the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial,1,2 the gradient in mortality (6-3% for tissue plasminogen activator [tPA], 7-0% for combined tPA and streptokinase, and 7-3% for streptokinase) paralleled the 90-minute coronary artery patency rates observed on angiography (81%, 73%, and 57%, respectively). To optimise reperfusion, primary angioplasty and several pharmacological adjuncts to thrombolysis are being evaluated. Meanwhile many communities have devised schemes to enhance patient awareness of myocardial infarction and thereby reduce delays in seeking medical attention. Hospitals have also introduced protocols to reduce treatment delays after

admission, What medical treatments might augment coronary A meta-analysis of thirty-two angiographic trials after tPA or streptokinase showed that aspirin achieved better 90-minute coronary patency rates than no aspirin (72% vs 63%, p<005).3 However, platelet adherence and release of growth factors are not affected by aspirin.’ Platelet aggregation, mediated by fibrinogen linking via the glycoprotein IIb/IIIa receptor, can occur even when the arachidonic acid pathway is completely blocked by aspirin. The importance of this receptor has been highlighted in randomised clinical trials which show that glycoprotein IIb/IIIa receptor antagonists, when administered with aspirin and heparin, result in

patency?